Somatic hypermutation of variable (V) genes, which encode a portion of immunoglobulin molecules, occurs at a frequency that is a million times greater than mutation in other genes. The molecular mechanism that introduces these mutations is unknown. The project has three major aims. The first goal was to study hypermutation in mice deficient for DNA repair enzymes to see if the frequency and pattern of mutation was different from wildtype mice. Mutation in V genes from mice deficient for the OGG1 base excision repair protein, MLH1 mismatch repair protein, and ATM kinase protein was similar to that of wildtype mice, indicating that neither of these repair proteins is involved in generating hypermutation. The second goal was to determine which DNA polymerases are expressed in B lymphocytes undergoing mutation. DNA polymerases alpha, beta, delta, epsilon and zeta are expressed in the rapidly dividing cells from germinal centers, and they could all be candidates for the enzyme introducing mutations. However, polymerases alpha and epsilon are not expressed by B cells outside of germinal centers, suggesting that these cells are resting and are deficient for DNA repair that utilizes polymerase epsilon. The third goal was to analyze hypermutation in V genes from old and young humans to determine if the frequency or pattern of mutation changes with age. The frequency of mutation was identical in both groups, indicating that old humans have hypermutated antibodies with high affinity for antigens. The spectra of mutation and microsatellite instability in old humans was different than that of young humans, suggesting that mismatch repair decreases with age. - antibody, B cell, hypermutation, DNA repair, DNA polymerase, aging